Douglas Lauffenburger

Molecular cell bioengineering: the application of engineering approaches to develop quantitative understanding of cell function in terms of fundamental molecular properties, and to apply this understanding for improved design of cell-based technologies. Our group focuses on elucidating important aspects of receptor-mediated regulation of mammalian blood and tissue cell behavioral functions such as proliferation, adhesion, migration, and macromolecular transport. A central paradigm of our work is development and testing of mechanistic models-- based on principles from engineering analysis and synthesis -- for receptor regulation of cell function by exploiting techniques of molecular biology to alter parameters characterizing receptor or ligand properties in well-characterized cell systems. Quantitative experimental assays are used to measure cell function and receptor/ligand interaction parameters. Problems are motivated by health care technologies of interest to pharmaceutical and biotechnological companies.

Sarkar, C.A., K. Lowenhaupt, T. Horan, T.C. Boone, B. Tidor, and D.A. Lauffenburger, "Rational Cytokine Design for Increased Lifetime and Enhanced Potency Using pH-Activated 'Histidine Switching'", Nature Biotech. 20: 908-913 (2002).

Dewitt, A., T. Iida, H.-Y. Lam, V. Hill, H.S. Wiley, and D.A. Lauffenburger, "Affinity Regulates Spatial Range of EGF Receptor Autocrine Ligands", Develop. Biol. 250: 305-316 (2002).

Sarkar, C.A. and D.A. Lauffenburger, "Cell-Level Pharmacokinetic Model of GCSF: Implications for Ligand Lifetime and Potency in Vivo", Molec. Pharmacol. 63: 147-158 (2003).

Hendriks, B., L.K. Opresko, H.S. Wiley, and D.A. Lauffenburger, "Co-Regulation of EGFR/HER2 Levels and Locations: Quantitative Analysis of HER2 Overexpression Effects", Cancer Res. 63: 1130-1137 (2003).

Ricci, M.S., C.A. Sarkar, E.M. Fallon, D.A. Lauffenburger, and D.N. Brems, "pH Dependence of Structural Stability of IL-2 and GCSF", Protein Sci. 12: 1030-1038 (2003).

Sarkar, C.A., Lowenhaupt, K., Wang, P.J., Horan, T., and D.A. Lauffenburger, "Parsing the Effects of Binding, Signaling, and Trafficking on the Mitogenic Potency of GCSF Analogs", Biotech. Progr. 19: 955-964 (2003).

Hendriks, B., L.K. Opresko, H.S. Wiley, and D.A. Lauffenburger, "Quantitative Analysis of HER2-Mediated Effects on HER2 and EGFR Endocytosis: Distribution of Homo- and Hetero-dimers Depends on Relative HER2 Levels", J. Biol. Chem. 278: 23343-23351 (2003).

Cheng, C., D.A. Lauffenburger, and T. Morales, "Motile Chondrocytes: Migration Properties and Synthesis of Collagen II", Osteoarthr. Cart. 11: 603-612 (2003).

Mamoune, A., J.-H. Luo, D.A. Lauffenburger, and A. Wells, "Calpain-2 as a Target for Limiting Prostate Cancer Invasion", Cancer Res. 63: 4632-4640 (2003).

Janes, K.A., J.G. Albeck, L.X. Peng, P.K. Sorger, D.A. Lauffenburger, and M.B. Yaffe, "High-Throughput Multiplex Kinase Assay for Monitoring Information Flow in Signaling Networks: Application to Sepsis-Apoptosis", Molec. Cell. Proteomics 2: 463-473 (2003).

Hendriks, B., H.S. Wiley, and D.A. Lauffenburger, "HER2-Mediated Effects on EGFR Endosomal Sorting: Analysis of Biophyical Mechanisms", Biophys. J. 85: 2732-2745 (2003).

Viswanathan, S., T. Benatar, M. Mileikovsky, D.A. Lauffenburger, A. Nagy, and P.W. Zandstra, "Supplementation-Dependent Differences in the Rates of Embryonic Stem Cell Self-Renewal, Differentiation, and Apoptosis", Biotech. Bioeng. 84: 505-517 (2003).

Rao, B.J., A.T. Girvin, T. Ciardelli, D.A. Lauffenburger, and K.D. Wittrup, "Interleukin-2 Mutants with Enhanced a-Receptor Subunit Binding Affinity", Protein Eng. 16: 1081-10877 (2003).

Maly, I., H.S. Wiley, and D.A. Lauffenburger, "Self-Organization of Polarized Cell Signaling via Autocrine EGFR Circuits: Computational Model Analysis", Biophys. J. 86: 10-22 (2004).

Prudhomme, W., K. Duggar, G.Q. Daly, P.W. Zandstra, and D.A. Lauffenburger, "Multi-Variate Proteomic Analysis of Murine Embryonic Stem Cell Self-Renewal vs Differentiation Behavior", Proc. Natl. Acad. Sci. USA 101: 2900-2905 (2004).

Iwabu, A., K. Smith, F.D. Allen, D.A. Lauffenburger, and A. Wells, "EGF Induces Fibroblast Contractility and Motility via a PKCd-Dependent Pathway", J. Biol. Chem. (2004, accepted).

Janes, K.A., J. R. Kelly, S. Gaudet, J.G.Albeck, P.K. Sorger, and D.A. Lauffenburger, "Cue-Signal-Response Analysis of TNF-Induced Apoptosis by Partial Least Squares Regression of Dynamic Multi-Variate Signaling Network Measurements", J. Comp. Biol. (2004, accepted).

Prudhomme, W., K.H. Duggar, and D.A. Lauffenburger, "Kinetic Model for Deconvolution of Murine Embryonic Stem Cell Self-Renewal and Differentiation Responses to Cytokines and Extracellular Matrix", Biotech. Bioeng. (2004, accepted).

Tschumperlin, D.J., G. Dai, I.V. Maly, L.H. Laiho, A.K. McVittie, P.T. So, D.A. Lauffenburger, R.D. Kamm, and J.M. Drazen, "Mechanotransduction via Growth Factor Shedding into a Compliant Extracellular Space", Nature (2004, accepted).

Hendriks, B.S., A. Wells, H.S. Wiley, and D.A. Lauffenburger, "Relative Contributions of Receptor Interactions and Endocytic Trafficking Processes in Governing ERK Activation via the EGFR-HER2 System", J. Biol. Chem. (2004, submitted).

Lu, H., L.Y. Koo, D.A. Lauffenburger, L.G. Griffith, and K.F. Jensen, "Microfluidic Shear Devices for Quantitative Analysis of Cell Adhesion", Analyt. Chem. (2004, submitted).

Rao, B.M., I. Driver, D.A. Lauffenburger, and K.D. Wittrup, "IL-2 Variants Engineered for Increased IL-2Ra Affinity Exhibit Increased Potency Arising from a Cell Surface Ligand Reservoir Effect", Molec. Pharmacol. (2004, submitted).

Zaman, M., R.D. Kamm, P.T. Matsudaira, and D.A. Lauffenburger, "Computational Model for Cell Migration in 3-Dimensional Matrices", Biophys. J. (2004, submitted).

Maly, I., R.T. Lee, and D.A. Lauffenburger, "A Model for Mechanotransduction in Cardiac Muscle: Effects of Extracellular Matrix Deformation on Autocrine Signaling", Ann. Biomed. Eng. (2004, submitted).